Olezarsen safely lowers triglycerides in patients with familial chylomicronemia syndrome
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Key takeaways:
- Olezarsen lowered triglyceride levels at 6 months in patients with familial chylomicronemia syndrome.
- The safety profile of olezarsen was much better than that of volanesorsen, a predecessor drug.
Olezarsen, an antisense oligonucleotide targeting mRNA for apolipoprotein C-III, lowered triglycerides at 6 months for patients with familial chylomicronemia syndrome without excessive adverse events, researchers reported.
The results of the phase 3 BALANCE trial of olezarsen (Ionis Pharmaceuticals) for patients with familial chylomicronemia syndrome (FCS) were presented at the National Lipid Association (NLA) Scientific Sessions. They had previously been published in The New England Journal of Medicine.
FCS is a rare genetic disease causing severe hypertriglyceridemia, and patients with it are at dramatically increased risk for acute pancreatitis and do not respond to conventional triglyceride-lowering treatments, Christie M. Ballantyne, MD, FACC, FACP, FAHA, FNLA, chief of the section of cardiovascular research and professor of medicine at Baylor College of Medicine, said during a presentation.
The trial included 66 patients with genetically identified FCS and fasting triglycerides 880 mg/dL or greater, and was designed to include at least 65% of patients who had at least one acute pancreatitis event within 10 years of enrollment.
The patients were randomly assigned to olezarsen 50 mg (mean age, 43 years; 71% women), olezarsen 80 mg (mean age, 48 years; 50% women) or placebo (mean age, 44 years; 52% women) once every 4 weeks. Triglyceride levels at baseline averaged more than 2,600 mg/dL. The primary endpoint was fasting triglyceride level at 6 months.
“For those of you who are familiar with volanesorsen, [olezarsen] is an improved second- or third-generation drug, with lower dosages used in this study, 50 mg or 80 mg once a month vs. 300 mg weekly,” Ballantyne said during the presentation. “It ends up being more specific.”
Despite an advisory panel recommendation in favor of it, the FDA declined to approve volanesorsen (Akcea) for patients with FCS due to concerns about risk for thrombocytopenia and other adverse events.
At 6 months, patients assigned olezarsen 80 mg had lower triglyceride levels compared with those assigned placebo (least-squares mean difference [LSMD], –43.5%; P < .001), whereas those assigned olezarsen 50 mg had numerically but not significantly lower triglyceride levels than the placebo group (LSMD, –22.4%; P = .077), Ballantyne, who became president of the NLA during the meeting, said during the presentation.
Both olezarsen groups had lower fasting ApoC-III levels at 6 months compared with the placebo group (LSMD for olezarsen 50 mg vs. placebo, –65.5%; LSMD for olezarsen 80 mg vs. placebo, –73.7%), he said.
Time to first pancreatitis event was longer in the olezarsen groups compared with the placebo group, Ballantyne said, noting that seven patients in the placebo group had 11 pancreatitis events compared with one patient having one event in each of the olezarsen groups (mean RR for pooled olezarsen groups vs. placebo group = 0.12; 95% CI, 0.022-0.656).
There were no drug-related serious adverse events in any group, and the rate of any serious adverse events was higher in the placebo group compared with the olezarsen groups, Ballantyne said.
“Safety was much improved from the prior version, volanesorsen,” Ballantyne said during the presentation. “There were fewer injection-site reactions, there were no significant changes in regard to the liver, and most importantly, there were no clinically meaningful changes in platelet count or in measures of hepatic and renal function. That’s important because what we have seen is when you give a high dose of something that isn’t specific to the liver, you ended up having some patients developing thrombocytopenia. Here, you see the efficacy without the side effects. That is the beauty of biotechnology.”
Reference:
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Ballantyne CM, et al. Session V – Oral poster presentations. Presented at: National Lipid Association Scientific Sessions; May 30-June 2, 2024; Las Vegas (hybrid meeting).
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